Autosomal Recessive CMT 4H : Mutations in FGD4 Encoding the Rho GDP/GTP Exchange

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Am J Hum Genet. 2007 Jul;81(1):1-16.

Mutations in FGD4 Encoding the Rho GDP/GTP Exchange Factor FRABIN

Cause Autosomal Recessive Charcot-Marie-Tooth Type 4H.

Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio

I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Megarbane A,

Haase G, Levy N. INSERM U491, Faculte de Medecine de la Timone,

Marseille, France.

Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically

heterogeneous group of hereditary motor and sensory neuropathies

characterized by muscle weakness and wasting, foot and hand

deformities, and electrophysiological changes. The CMT4H subtype is

an autosomal recessive demyelinating form of CMT that was recently

mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two

consanguineous families of Mediterranean origin, by homozygosity

mapping. We report here the identification of mutations in FGD4,

encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in

both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF),

specific to Cdc42, a member of the Rho family of small guanosine

triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play

a key role in regulating signal-transduction pathways in eukaryotes.

In particular, they have a pivotal role in mediating actin

cytoskeleton changes during cell migration, morphogenesis,

polarization, and division. Consistent with these reported

functions, expression of truncated FRABIN mutants in rat primary

motoneurons and rat Schwann cells induced significantly fewer

microspikes than expression of wild-type FRABIN.

To our knowledge, this is the first report of mutations in a Rho GEF

protein being involved in CMT.